Leishmania major infections in (C57BL/6 x BALB/c) Fl mice are either healing or non-healing, depending on the site of parasite inoculation. Thus, lesions in the footpad spontaneously resolve whereas lesions in the dorsal skin at the base of the tail are progressive and ultimately fatal. Based on previous evidence that healing and non-healing infections correlated with the activation of Thl versus Th2 CD4+ cells, site-specific infections in Fl mice will be analyzed to determine mechanisms which may influence the development of divergent patterns of T helper subset activation in the same mouse. Since Fl mice, in contrast to parental strains, develop mixed Thl/Th2 responses during early stages of infection, studies will focus on events which modify Thl vs Th2 induction, as well as events which regulate the divergence of mixed responses toward dominance of a specific subset. Specifically, efforts will be made to determine how host antibody may influence the induction of Thl/Th2 cells as well as regulate established Thl/Th2 responses. A similar role for APC populations in the induction and regulation of Th subsets will be sought. In addition, since macrophage products such as IL-1 and PGE2 have been shown to influence disease progression, studies will determine whether these factors simply promote inflammation, or also influence Th subset activation or expansion. Finally, infections in Fl mice will be utilized to determine whether CD8+ cells are important in the development of acquired resistance to L. major and whether these cells are a significant source of IFN-gamma production during infection.